Medicaments

ABSTRACT

The invention relates to the use of compounds of formula (I) ##STR1## wherein Im represents an imidazolyl group of formula: ##STR2## and R 1  represents a hydrogen atom or a group selected from C 1-6  alkyl, C 3-6  alkenyl, C 3-10  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4  alkyl, phenyl, phenylC 1-3  alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, --CO 2  R 5 , --COR 5 , --CONR 5  R 6  or --SO 2  R 5  (wherein R 5  and R 6 , which may be the same or different, each represents a hydrogen atom, a C 1-6  alkyl or C 3-7  cycloalkyl group, or a phenyl or phenylC 1-4  alkyl group, in which the phenyl group is optionally substituted by one or more C 1-4  alkyl, C 1-4  alkoxy or hydroxy groups or halogen atoms, with the proviso that R 5  does not represent a hydrogen atom when R 1  represents a group --CO 2  R 5  or --SO 2  R 5 ); 
     one of the groups represented by R 2 , R 3  and R4 is a hydrogen atom or a C 1-6  alkyl, C 3-7  cycloalkyl, C 3-6  alkenyl, phenyl or phenylC 1-3  alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C 1-6  alkyl group; 
     and n represents 2 or 3, 
     and physiologically acceptable salts and solvates thereof for the manufacture of a medicament for the treatment of depression.

This application is a continuation of application Ser. No. 07/800,982,filed Dec. 2, 1991, now abandoned, which is a continuation ofapplication Ser. No. 07/698,902, filed May 13, 1991, now abandoned,which is a continuation of application Ser. No. 07/538,939, filed Jun.15, 1990, now abandoned, which is a continuation of application Ser. No.07/400,345, filed Aug. 31, 1989, now abandoned.

This invention relates to a further medical use for a group ofheterocyclic compounds and pharmaceutical compositions containing them.In particular it relates to the use of certain lactam derivatives in thetreatment of depression.

Compounds which are antagonists of 5-HT at 5-HT₃ receptors have beendescribed previously for use in the treatment of depression in, forexample, published European Patent Applications Nos. 276559 and 278173,and in German Offenlegungsschrift No. 3740352.

The present invention relates to the use, in this indication, of aparticular group of compounds which are antagonists of 5-HT at 5-HT₃receptors, as defined by the general formula (I). ##STR3## In the aboveformula Im represents an imidazolyl group of formula: ##STR4## and R¹represents a hydrogen atom or a group selected from C₁₋₆ alkyl, C₃₋₆alkenyl, C₃₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl,phenyl, phenylC₁₋₃ alkyl, phenylmethoxymethyl, phenoxyethyl,phenoxymethyl, --CO₂ R⁵, --COR⁵, --CONR⁵ R⁶ or --SO₂ R⁵ (wherein R⁵ andR⁶ , which may be the same or different, each represents a hydrogenatom, a C₁₋₆ alkyl or C₃₋₇ cycloalkyl group, or a phenyl or phenylC₁₋₄alkyl group, in which the phenyl group is optionally substituted by oneor more C₁₋₄ alkyl, C₁₋₄ alkoxy or hydroxy groups or halogen atoms, withthe proviso that R⁵ does not represent a hydrogen atom when R¹represents a group --CO₂ R⁵ or --SO₂ R⁵);

one of the groups represented by R², R³ and R⁴ is a hydrogen atom or aC₁₋₆ alkyl, C₃₋₇ cycloakyl, C₃₋₆ alkenyl, phenyl or phenylC₁₋₃ alkylgroup, and each of the other two groups, which may be the same ordifferent, represents a hydrogen atom or a C₁₋₆ alkyl group;

and n represents 2 or 3.

Suitable physiologically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with organic or inorganicacids for example, hydrochlorides, hydrobromides, sulphates, alkyl- orarylsulphonates (e.g. methanesulphonates or p-toluenesulphonates),phosphates, acetates, citrates, succinates, tartrates, fumarates andmaleates. The solvates may, for example, be hydrates.

Compounds defined by the general formula (I) are the subject ofpublished European Patent Application No. 306323, which was unpublishedat the priority date of the present application.

The compounds of formula (I) are potent and selective antagonists of5-hydroxytryptamine (5-HT) at `neuronal` 5-HT receptors of the typelocated on terminals of primary afferent nerves. Receptors of this typeare now designated as 5-HT₃ receptors and are also present in thecentral nervous system. 5-HT occurs widely in the neuronal pathways inthe central nervous system and disturbance of these 5-HT containingpathways is known to alter behavioural syndromes such as mood,psychomotor activity, appetite and memory.

The potent and selective antagonism of 5-HT at 5-HT₃ receptors bycompounds for use according to the invention has been demonstrated bytheir ability to inhibit 3-(5-methyl-1H-imidazol-4-yl)-1-[1-(methylt₃)-1H-indol-3-yl]-1-propanone binding in ratentorhinal cortex homogenates (following the general procedure describedby G. Kilpatrick et al. in Nature, 1987, 330, 746), and/or by theirability to inhibit the 5-HT-induced depolarisation of the rat isolatedvagus nerve preparation.

Compounds which are antagonists of 5-HT at 5-HT₃ receptors, such as thecompounds of formula (I), are of use in the treatment of a human oranimal subject suffering from anxiety, a psychotic disorder such asschizophrenia, or nausea and vomiting. The compounds are also useful inthe treatment of gastric stasis; symptoms of gastrointestinaldysfunction such as occur with dyspepsia, peptic ulcer, refluxoesophagitis, flatulence and irritable bowel syndrome; migraine; andpain.

We have now found that the compounds of formula (I) and theirphysiologically acceptable salts and solvates, may be used in thetreatment of depression.

Accordingly the invention provides a method of treatment of a human oranimal subject suffering from depression, which comprises administeringto a human or animal subject an effective amount of a compound offormula (I) or a physiologically acceptable salt or solvate thereof. Thetreatment of humans is particularly important.

References in this specification to treatment include prophylactictreatment as well as the acute alleviation of symptoms.

The use of all optical isomers of compounds of general formula (I) andtheir mixtures including the racemic mixtures thereof, and all thegeometric isomers of compounds of formula (I), is embraced by theinvention.

A particular group of compounds of formula (I) for use according to theinvention is that wherein R¹ represents a hydrogen atom or a groupselected from C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₁₀ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkylC₁₋₄ alkyl, phenyl or phenylC₁₋₃ alkyl (n and Im being asdefined in formula (I)).

A preferred group of compounds of formula (I) for use according to theinvention is that wherein R¹ represents a hydrogen atom or a C₁₋₄ alkyl,C₃₋₄ alkenyl, C₃₋₄ alkynyl, C₅₋₆ cycloalkyl, C₅₋₆ cycloalkylmethyl,phenylC₁₋₂ alkyl, phenylmethoxymethyl, N,N-diC₁₋₃ alkylcarboxamido orC₁₋₃ alkylsulphonyl group; R² represents a hydrogen atom; and R³ and R⁴each represent a hydrogen atom or a C₁₋₃ alkyl group.

A particularly preferred group of compounds of formula (I) for useaccording to the invention is that wherein R¹ represents a methyl,n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N,N,dimethylcarboxamido group; R² and R³ each represent a hydrogen atom;and R⁴ represents a methyl group.

Within the above preferred and particularly preferred groups ofcompounds, an especially important group of compounds is that in which nrepresents 2.

Preferred compounds for use according to the invention are:

2,3,4,5-tetrahydro-5-(phenylmethyl)-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one;

5-cyclopentyl-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one;

2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-propyl-1H-pyrido[4,3-b]indol-1-one;

5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one;

3,4,5,6-tetrahydro-6-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]azepino[4,3-b]indol-1(2H)-one;

2,3,4,5-tetrahydro-N,N-dimethyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1-oxo-5H-pyrido[4,3-b]indole-5-carboxamide;

2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-(2-propynyl)-1H-pyrido[4,3-b]indol-1-one;

and their physiologically acceptable salts and solvates.

A particularly preferred compound for use according to the invention is2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-oneand its physiologically acceptable salts and solvates. Preferred saltsof this compound are the hydrochloride and maleate, of which thehydrochloride is particularly preferred.

In a further aspect, the invention provides a pharmaceutical compositionwhich comprises an effective amount of a compound of formula (I) or aphysiologically acceptable salt or solvate (e.g. hydrate) thereof, foruse in human or veterinary medicine, particularly human medicine, forthe treatment of depression.

In a yet further aspect, the invention provides for the use of acompound of formula (I) or a physiologically acceptable salt or solvatethereof, for the manufacture of a medicament for the treatment ofdepression.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers of excipients.

Thus the compounds of formula (I) and their physiologically acceptablesalts and solvates may be formulated for oral, buccal, parenteral,rectal or transdermal administration or in a form suitable foradministration by inhalation or insufflation (either through the mouthor the nose). Oral administration is preferred.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection e.g. by bolus injection or continuousinfusion. Formulation for injection may be presented in unit dosage forme.g. in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The compounds of formula (I) may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as depot preparations. Such long acting formulationsmay be administered by implantation (for example subcutaneously,transcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compounds of formula (I) may be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

A proposed dose of a compound of formula (I) for use according to theinvention for administration to man (of approximately 70 kg body weight)is 0.001 to 100 mg, for example 0.01 to 50 mg, of the active ingredientper unit dose, expressed as the weight of free base. A preferred dose ofactive ingredient per unit dose is 0.001 to 10 mg. The unit dose may beadministered, for example, 1 to 4 times per day. The dose will depend onthe route of administration. It will be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand weight of the patient as well as the severity ofthe condition to betreated.

Compounds of general formula (I) and physiologically acceptable salts orsolvates thereof, may be prepared by the methods described in publishedEuropean Patent Application No. 306323.

The following examples illustrate the preparation of2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-oneand its hydrochloride salt, covered by formula (I). Temperatures are in° C. Thin layer chromatograpy (t.l.c.) was carried out on silica.Organic extracts were dried, where indicated, over magnesium sulphate orsodium sulphate.

EXAMPLE 12,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one

A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one(400 mg) in dry dimethoxyethane (50 ml) was treated with sodium hydride(60% dispersion in oil; 100 mg), and the mixture was stirred at 60°under nitrogen for 6 h.4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (474 mg) wasadded and the reaction mixture was stirred at 60° under nitrogenovernight. 2N Hydrochloric acid (10 ml) and water (10 ml) were thenadded, and the mixture was heated at reflux for 6 h. After cooling, themixture was basified with 2N sodium hydroxide and the resulting mixturewas extracted with ethyl acetate (2×50 ml). The combined, dried organicextracts were concentrated onto flash column chromatography (FCC) silicaand purified by FCC eluting with dichloromethane:ethanol: 0.88 ammonia(150:8:1) to give the title compound (352 mg) as a solid, t.l.c.(dichloromethane:ethanol:0.88 ammonia 100:8:1) Rf 0.28. ¹ H-N.m.r.(DMSO-d₆): δ 2.2 (3H,s), 3.04 (2H,t), 3.62 (2H,t), 3.72 (3H,s), 4.53(2H,s), 7.1-7.28 (2H,m), 7.43 (1H,s), 7.47-7.55 (1H,dd), 7.94-8.03(1H,dd).

EXAMPLE 22,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1-H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-onehydrochloride

2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one(1.00 g) was suspended in ethanol (40 ml) and concentrated hydrochloricacid (1.00 ml) was added. The mixture was warmed to 40° and charcoal(0.25 g) was added. The resulting suspension was stirred and warmed for5 min. and then filtered. The filtrate was evaporated in vacuo to ca. 20ml and was allowed to cool to 20°. Ether (40 ml) was added with stirringover 5 min., and the mixture was stored at 4° overnight. The resultingprecipitate was filtered off, washed with ether (2×10 ml), dried invacuo at room temperature for 2 h and then at 70° for 7 h to give thetitle compound (0.95 g), m.p. 288°-291°.

Analysis Found: C,61.4; H,5.8; N,16.7; Cl, 10.7; C₁₇ H₁₈ N₄ O.HClrequires C,61.7; H,5.8; N,16.9; Cl, 10.7%

The following examples illustrate pharmaceutical formulations for useaccording to the invention, containing, as the active ingredient,2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-1-yl)methyl]-1H-pyrido-[4,3-b]indol-1-one(Compound A) in the form of its free base or hydrochloride salt (1.124 gof the hydrochloride is equivalent to 1 g of the free base). Otherphysiologically acceptable salts and/or solvates of Compound A, andother compounds of formula (I) and their physiologically acceptablesalts and/or solvates may be formulated in a similar manner.

TABLETS FOR ORAL ADMINISTRATION

Tablets may be prepared by the normal methods such as direct compressionor wet granulation.

The tablets may be film coated with suitable film forming materials,such as hydroxypropyl methylcellulose, using standard techniques.Alternatively the tablets may be sugar coated.

Direct Compression

    ______________________________________                                        (i)    Tablet               mg/tablet                                         ______________________________________                                        Compound A free base    0.50                                                  Calcium Hydrogen Phosphate BP*                                                                        87.25                                                 Croscarmellose Sodium NF                                                                              1.80                                                  Magnesium Stearate BP   0.45                                                  Compression weight      90.00                                                 ______________________________________                                         *of a grade suitable for direct compression.                             

The active ingredient is passed through a 60 mesh sieve, blended withthe calcium hydrogen phosphate, croscarmellose sodium and magnesiumstearate. The resultant mix is compressed into tablets using a ManestyF3 tablet machine fitted with 5.5 mm, flat bevelled edge punches.

    ______________________________________                                        (ii)    Tablet             mg/tab1et                                          ______________________________________                                        Compound A hydrochloride                                                                             0.562                                                  Microcystalline cellulose NF                                                                         31.250                                                 Lactose (anhydrous) NF 111.303                                                Pregelatinised maize starch BP                                                                       6.250                                                  Magnesium Stearate     0.625                                                  Compression weight     150.0                                                  ______________________________________                                         *of a grade suitable for direct compression.                             

The active ingredient is passed through a 60 mesh sieve, blended withthe lactose, microcystalline cellulose, pregelatinised maize starch andmagnesium stearate. The resultant mix is compressed into tablets using asuitable tablet machine fitted with 7.0 mm, normal concave punches.

    ______________________________________                                        Sub-Lingual Tablet  mg/tab1et                                                 ______________________________________                                        Compound A hydrochloride                                                                          0.562                                                     Compressible Sugar NF                                                                             63.938                                                    Magnesium Stearate BP                                                                             0.5                                                       Compression Weight  65.0                                                      ______________________________________                                    

The active ingredient is sieved through a suitable sieve, blended withthe excipients and compressed using suitable punches.

Tablets of other strengths may be prepared by altering either the ratioof active ingredient to excipients or the compression weight and usingpunches to suit.

Wet Granulation

    ______________________________________                                        Conventional Tablet  mg/tab1et                                                ______________________________________                                        Compound A hydrochloride                                                                           0.562                                                    Lactose BP           152.938                                                  Starch BP            30.000                                                   Pregelatinised Maize Starch BP                                                                     15.000                                                   Magnesium Stearate BP                                                                              1.500                                                    Compression Weight   200.0                                                    ______________________________________                                    

The active ingredient is sieved through a suitable sieve and blendedwith lactose, starch and pregelatinised maize starch. Suitable volumesof purified water are added and the powders are granulated. Afterdrying, the granules are screened and blended with the magnesiumstearate. The granules are then compressed into tablets using 8 mmdiameter punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to lactose or the compression weight and using punchesto suit.

    ______________________________________                                        Sub-Lingual Tablet  mg/tablet                                                 ______________________________________                                        Compound A hydrochloride                                                                          0.562                                                     Mannitol BP         58.438                                                    Hydroxypropylmethylcellulose                                                                      5.000                                                     Magnesium Stearate BP                                                                             1.000                                                     Compression Weight  65.0                                                      ______________________________________                                    

The active ingredient is sieved through a suitable sieve and blendedwith the mannitol and hydroxypropylmethylcellulose. Suitable volumes ofpurified water are added and the powders are granulated. After drying,the granules are screened and blended into tablets using suitablepunches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to mannitol or the compression weight and punches tosuit.

    ______________________________________                                        CAPSULES            mg/capsule                                                ______________________________________                                        Compound A hydrochloride                                                                          0.562                                                     *Starch 1500        98.438                                                    Magnesium Stearate BP                                                                             1.000                                                     Fill Weight         100.0                                                     ______________________________________                                         *a form of directly compressible starch.                                 

The active ingredient is sieved and blended with the excipients. The mixis filled into size No. 2 hard gelatin capsules using suitabledmachinery. Other doses may be prepared by altering the fill weight an ifnecessary changing the capsule size to suit.

Syrup

This may be either a sucrose or sucrose free presentation.

    ______________________________________                                        A.    Sucrose Syrup       mg/5 ml dose                                        ______________________________________                                        Compound A hydrochloride  0.562                                               Sucrose BP                2750.0                                              Glycerine BP              500.0                                               Buffer                                                                        Flavour                                                                       Colour                    as required                                         Preservative                                                                  Purified Water BP         to 5.0 ml                                           ______________________________________                                    

The active ingredient, buffer, flavour, colour and preservative aredissolved in some of the water and the glycerine is added. The remainderof the water is heated to dissolve the sucrose and is then cooled. Thetwo solutions are combined, adjusted to volume and mixed. The syrup isclarified by filtration.

    ______________________________________                                        B.    Sucrose-Free          mg/5 ml dose                                      ______________________________________                                        Compound A hydrochloride                                                                              0.562                                                 Hydroxypropylmethylcellulose USP                                                                      22.5                                                  (viscosity type 4000)                                                         Buffer                                                                        Flavour                                                                       Colour                      as required                                       Preservative                                                                  Sweetener                                                                     Purified Water BP           to 5.0 ml                                         ______________________________________                                    

The hydroxypropylmethylcellulose is dispersed in hot water, cooled andthen mixed with an aqueous solution containing the active ingredient andthe components of the formulation. The resultant solution is adjusted tovolume and mixed. The syrup is clarified by filtration.

INJECTION FOR INTRAVENOUS ADMINISTRATION

    ______________________________________                                                        mg/ml                                                         ______________________________________                                        (i)                                                                           Compound A free base                                                                            0.05      0.5                                               Sodium Chloride BP                                                                              as required                                                                             as required                                       Water for Injection                                                                             1.0 ml     1.0 ml                                           (ii)                                                                          Compound A hydrochloride                                                                        0.0562    0.562                                             Sodium Chloride BP                                                                              as required                                                                             as required                                       Water for Injection BP to                                                                       1.0 ml     1.0 ml                                           ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted, using acid or alkali, to that of optimumstability and/or facilitate solution of the active ingredient.Alternatively, suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate sizeampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.Alternatively, the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen or other suitable gas.

SUPPOSITORY

    ______________________________________                                        (i)     Compound A free base 0.5    mg                                                *Witepsol H15 to     1.0    g                                         (ii)    Compound A hydrochloride                                                                           0.562  mg                                                *Witepsol H15 to     1.0    g                                         ______________________________________                                         *Witepsol H15 is a proprietary grade of Adeps Solidus Ph. Eur.           

A suspension of the active ingredient is prepared in the molten Witepsoland filled, using suitable machinery, into 1 g size suppository moulds.

We claim:
 1. A method for the treatment of depression which comprisesadminstering to a human or animal subject suffering from depression aneffective amount for the treatment of said depression of a compound offormula (I) ##STR5## wherein Im represents an imidazolyl group offormula: ##STR6## and R¹ represents a hydrogen atom or a group selectedfrom C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, phenyl, phenylC₁₋₃ alkyl, phenylmethoxymethyl,phenoxyethyl, phenoxymethyl, --CO₂ R⁵, --COR⁵, --CONR⁵ R⁶ or --SO₂ R⁵(wherein R⁵ and R⁶, which may be the same or different, each representsa hydrogen atom, a C₁₋₆ alkyl or C₃₋₇ cycloalkyl group, or a phenyl orphenylC₁₋₄ alkyl group, in which the phenyl group is optionallysubstituted by one or more C₁₋₄ alkyl, C₁₋₄ alkoxy or hydroxy groups orhalogen atoms, with the proviso that R⁵ does not represent a hydrogenatom when R¹ represents a group --CO₂ R⁵ or --SO₂ R⁵);one of the groupsrepresented by R², R³ and R⁴ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₆ alkenyl, phenyl or phenylC₁₋₃ alkyl group, and each ofthe other two groups, which may be the same or different, represents ahydrogen atom or a C₁₋₆ alkyl group; and n represents 2 or 3,or aphysiologically acceptable salt or solvate thereof as the activeingredient.
 2. A method according to claim 1 in which in the compound offormula (I) R¹ represents a hydrogen atom or a C₁₋₄ alkyl, C₃₋₄ alkenyl,C₃₋₄ alkynyl, C₅₋₆ cycloalkyl, C₅₋₆ cycloalkylmethyl, phenylC₁₋₂ alkyl,phenylmethoxymethyl, N,N-diC₁₋₃ alkylcarboxamido or C₁₋₃ alkylsulphonylgroup; R² represents a hydrogen atom; and R³ and R⁴ each represent ahydrogen atom or a C₁₋₃ alkyl group.
 3. A method according to claim 1 inwhich in the compound of formula (I) R¹ represents a methyl, n-propyl,prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl orN,N-dimethylcarboxamido group; R² and R³ each represent a hydrogen atom;and R⁴ represents a methyl group.
 4. A method according to claim 1 inwhich in the compound of formula (I), n is
 2. 5. A method according toclaim 1 in which said compound of formula (I) is selectedfrom2,3,4,5-tetrahydro-5-(phenylmethyl)-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one;5-cyclopentyl-2,34,5-tetrahydro-2-[5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one;2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-propyl-1H-pyrido[4,3-b]indol-1-one;5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one;3,4,5,6-tetrahydro-6-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-azepino[4,3-b]indol-1(2H)-one;2,3,4,5-tetrahydro-N,N-dimethyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1-oxo-5H-pyrido[4,3-b]indole-5-carboxamide;2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-(2-propynyl)-1H-pyrido[4,3-b]indol-1-one;andphysiologically acceptable salts and solvates thereof.
 6. A methodaccording to claim 1 in which said compound of formula (I) isadministered in the form of a medicament in a form adapted for oraladministration.
 7. A method according to claim 1 in which said compoundof formula (I) is administered in a unit dose of from 0.001 to 100 mg ofthe active ingredient.
 8. A method according to claim 1 in which saidcompound of formula (I) is administered in a unit dose of from 0.001 to10 mg of the active ingredient.
 9. A method according to claim 2 inwhich in the compound of formula (I) R¹ is C₁₋₄ alkyl.
 10. A methodaccording to claim 9 in which in the compound of formula (I), n is 1.11. A method for the treatment of depression which comprisesadministering to a human or animal subject suffering from depression aneffective amount for the treatment of said depression of2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-oneor a physiologically acceptable salt or solvate thereof.
 12. A methodaccording to claim 11 in which said compound is used in the form of itshydrochloride salt.
 13. A method according to claim 11 in which saidcompound is administered in the form of a medicament in a form adaptedfor oral administration.
 14. A method according to claim 11 in whichsaid compound is administered in a unit dose of from 0.001 to 100 mg ofthe active ingredient.
 15. A method according to claim 11 in which saidcompound is administered in a unit dose of from 0.001 to 10mg of theactive ingredient.